Manfred Jung's research while affiliated with University of Freiburg and other places
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Publications (399)
Inhibition of epigenetic regulators by small molecules is an attractive strategy for cancer treatment. Recently, we characterised the role of lysine methyltransferase 9 (KMT9) in prostate, lung, and colon cancer. Our observation that the enzymatic activity was required for tumour cell proliferation identified KMT9 as a potential therapeutic target....
The NAD+-dependent lysine deacylase Sirtuin2 (Sirt2) is involved in multiple pathological conditions, including cancer and targeting Sirt2 has thus received an increased interest for therapeutic purpose. Furthermore, addressing the ortholog from Schistosoma mansoni (SmSirt2) has been considered for the potential treatment of the neglected tropical...
Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)‐approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro inv...
Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off‐target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, seve...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class...
Intracellular pathogens exploit host cell functions to favor their own survival. In recent years, the subversion of epigenetic regulation has emerged as a key microbial strategy to modify host cell gene expression and evade antimicrobial immune responses. Using the protozoan parasite Leishmania as a model system, we have recently demonstrated that...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class...
Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects, which may be a reason to exclude many of them from further drug development. Prodrug design has shown promise as an approach to improve pharmacoki...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class...
Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Se...
The NAD+-dependent lysine deacylase Sirtuin2 (Sirt2) is involved in multiple pathological conditions, including cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purpose, including the ortholog from Schistosoma mansoni (SmSirt2) for the potential treatment of the neglected tropical disease schistosomiasis. We previousl...
Matteson homologations and a Pd-catalysed C–H functionalisation are key steps in the synthesis of highly selective HDAC1 inhibitor WF-3161.
![Figure 5. v/[S] plots of SIRT2 with F4 under different conditions. (A)...](publication/370118416/figure/fig5/AS:11431281150906058@1681927706427/v-S-plots-of-SIRT2-with-F4-under-different-conditions-A-The-kinetic-parameters-for_Q320.jpg)
Lysine deacetylases, like histone deacetylases (HDACs) and sirtuins (SIRTs), are involved in many regulatory processes such as control of metabolic pathways, DNA repair, and stress responses. Besides robust deacetylase activity, sirtuin isoforms SIRT2 and SIRT3 also show demyristoylase activity. Interestingly, most of the inhibitors described so fa...
For a long time, the development of bromodomain (BD) inhibitors (BDi) was almost exclusively related to the BET family. More recently, BDi for BDs outside the BET family have also been developed. Here we present a novel pan-BDi with micromolar affinities to various BDs, and nanomolar affinities to representatives of BD families I, II (Bromodomain a...
The Front Cover shows how Neglected Tropical Diseases including schistosomiasis don′t have effective strategies to fight the parasite infection. Only a few drugs for treating such diseases display selectivity against parasites over humans, and only some of them exhibit activity against all the parasite stages of life. In schistosomiasis, for exampl...
We developed a facile photoreductive and stereoselective β-aminoalkylation of a crowded enone by blue LED light irradiation using a wide variety of α-amino acids in order to access 5'-amino substituted...
Schistosoma mansoni HDAC8 is a reliable target to fight schistosomiasis, and several inhibitors have been reported in the literature up to now. Nevertheless, only a few displayed selectivity over the human deacetylases and some exhibited very low or no activity against parasite larvae and/or adult worms. We report here the in vitro enzyme and biolo...
Histone deacetylases are considered promising epigenetic targets for chemical protein degradation due to their diverse roles in physiological cellular functions and in the diseased state. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that hijack the cell’s ubiquitin-proteasome system (UPS). One of the promising targets for thi...
![As previously reported,[30,31] benzanilide‐based hydroxamic acids can...](publication/362792563/figure/fig1/AS:11431281244438716@1715944304146/As-previously-reported-30-31-benzanilide-based-hydroxamic-acids-can-be-used-to-modulate_Q320.jpg)
Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein...
In contrast to other sirtuins (NAD⁺-dependent class III lysine deacylases), inhibition of Sirt5 is poorly investigated, yet. Our present work is based on the recently identified Sirt5 inhibitor balsalazide, an approved drug with negligible bioavailability after oral administration. After gaining first insights into its structure-activity relationsh...
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc‐dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e. g.,...
Nicotinamide adenine dinucleotide (NAD⁺) is an important biomolecule with essential roles at the intersection of energy metabolism, epigenetic regulation and cell signalling. Synthetic analogues of NAD⁺ are therefore of great interest as chemical tools for medicinal chemistry, chemical biology and drug discovery. Herein, we report the chemical synt...
In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in sever...
Epigenetic modulators such as Lysine-specific Demethylase 1 (LSD1) and Histone Deacetylases (HDACs), are drug targets for cancer, neuropsychatric disease or inflammation but inhibitors of these enzymes exhibit considerable side effects. For a potential local treatment with reduced systemic toxicity, we present here soft drugs as new LSD1 and HDAC i...
Purpose
Multiple myeloma (MM) remains an incurable hematologic malignancy which ultimately develops drug resistance and evades treatment. Despite substantial therapeutic advances over the past years, the clinical failure rate of preclinically promising anti-MM drugs remains substantial. More realistic in vitro models are thus required to better pre...
The search of new therapeutic tools for the treatment of cancer is being a challenge for medicinal chemists. Due to their role in different pathological conditions, histone deacetylase (HDAC) enzymes are considered valuable therapeutic targets. HDAC6 is a well-investigated HDAC-class IIb enzyme mainly characterized by a cytoplasmic localization; HD...
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, especially cancer. Five HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement, e.g.,...
While histone deacetylases (HDACs) are known as modulators of epigenetic gene
regulation, they also control the activity of non-histone protein substrates. The
isozyme HDAC8 plays a role in inhibiting apoptosis and increasing cancer cell
proliferation. As a result, HDAC8 is considered a potential target in the treatment of
cancer forms such as T-ce...
Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are valid tools to assess HDAC functions. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are ill-defined. This lack of knowledge is due to a lack...
Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affin...
Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are valid tools to assess HDAC functions. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are ill-defined. This lack of knowledge is due to a lack...
Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affin...
Anti-parasitic treatment of neglected tropical diseases (NTDs) caused by cestodes such as echinococcosis and cysticercosis relies on a small number of approved anthelmintic drugs. Furthermore, the treatment is usually prolonged and often partially effective and not well tolerated by some patients. Therefore, the identification of novel drug targets...
The tubulin deacetylases Sirt2 and HDAC6 have been associated with the development of various diseases. Herein, we discuss recent approaches that enable cellular target engagement studies for these deacetylases and thus play a critical role in the evaluation of small molecule inhibitors of Sirt2 or HDAC6 as potential therapeutic agents.
Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers that fall into 4 classes. Histone deacetylase inhibitors (HDACi) are valid tools to assess HDAC functions. HDAC6 and HDAC10 belong to the class IIb subgroup of the HDAC family. The targets and biological functions of HDAC10 are ill-defined. This lack of knowledge is due to a lack...
In addition to involvement in epigenetic gene regulation, histone deacetylases (HDACs) regulate multiple cellular processes through mediating the activity of non-histone protein substrates. The knockdown of HDAC8 isozyme is associated with the inhibition of cell proliferation and apoptosis enhancement in several cancer cell lines. As shown in sever...
Sirtuin2 (Sirt2) with its NAD+-dependent deacetylase and defatty-acylase activities plays a central role in the regulation of specific cellular functions. Dysregulation of Sirt2 activity has been associated with the pathogenesis of many diseases, thus making Sirt2 a promising target for pharmaceutical intervention. Herein, we present new high affin...
In utero renal development is subject to maternal metabolic and environmental influences affecting long-term renal function and the risk of developing chronic kidney failure and cardiovascular disease. Epigenetic processes have been implicated in the orchestration of renal development and prenatal programming of nephron number. However, the role of...
Many membrane proteins utilize dimerization to transmit signals across the cell membrane via regulation of the lateral binding affinity. The complexity of natural membrane proteins hampers the understanding of this regulation on a biophysical level. We designed simplified membrane proteins from well-defined soluble dimerization domains with tunable...
Opioid receptors (ORs) have been observed as homo- and heterodimers, but it is unclear if the dimers are stable under physiological conditions, and whether monomers or dimers comprise the predominant fraction in a cell. Here, we use three live-cell imaging approaches to assess dimerization of ORs at expression levels that are 10–100 × smaller than...
Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens’ modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic dru...
Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An a...
Use of hypoxia-activated prodrugs has emerged as a strategy for selectively targeting tumors in hypoxic conditions harboring reductive environments. In this issue of Cell Chemical Biology, Skwarska et al. (2021) report a hypoxia-activated prodrug targeting histone deacetylases (lysine deacetylases, KDACs) selectively over normoxic cells with activi...
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylas...
The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity re...
A growing body of evidence suggests that low nephron numbers at birth can increase the risk of chronic kidney disease or hypertension later in life. Environmental stressors, such as maternal malnutrition, medication and smoking, can influence renal size at birth. Using metanephric organ cultures to model single-variable environmental conditions, mo...
The present invention relates to novel compounds of formula (I) as defined herein. The compounds are inhibitors of histone methyltransferases of the seven-beta-strand family, in particular of KMT9.
Background:
Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their asso...
In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products wa...
New Thailandepsin B pseudo‐natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium‐catalyzed hydrooxycarbony...
Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and s...
We have discovered the sirtuin‐rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD⁺‐dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so‐called proteolysis‐targeting chimera (PROTAC) enabled small...
Assessment of hematotoxicity from environmental or xenobiotic compounds is of notable interest and is frequently assessed via the colony forming unit (CFU) assay. Identification of the mode of action of single compounds is of further interest, as this often enables transfer of results across different tissues and compounds. Metabolomics displays on...
The role of epigenetic regulation is in large parts connected to cancer, but additionally, its therapeutic claim in neurological disorders has emerged. Inhibition of histone H3 lysine N-methyltransferase, especially G9a, has been recently shown to restore candidate genes from silenced parental chromosomes in the imprinting disorder Prader-Willi syn...
Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules and allow selective protein degradation by addressing the natural ubiquitin proteasome system. As this new strategy of chemically induced protein degradation can serve as a biological tool and provides new possibilities for drug discovery, it has been applied to a variety of...
We report here an extensive structure-activity relationship study of balsalazide, which was previously identified in a high-throughput screening as an inhibitor of Sirt5. To get a closer understanding why this compound is able to inhibit Sirt5, we initially performed docking experiments comparing the binding mode of a succinylated peptide as the na...
Endocrine disrupting compounds (EDC) are found ubiquitous in the human environment, displaying a highly relevant research topic. Here, the impact of EDC on the differentiation of primitive cells, e.g. hematopoiesis, is of particular interest. We therefore assessed the impact of di-2-ethylhexyl phthalate (DEHP) on erythroid, dendritic and neutrophil...
Assessment of hematotoxicity from environmental or xenobiotic compounds is of notable interest and is frequently assessed via the colony forming unit (CFU) assay. Identification of the mode of action of single compounds is of further interest, as such often enables transfer of results across different tissues and compounds. Metabolomics displays on...
Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the...
Histone deacetylases (HDACs) remove acetyl groups from histone proteins and are implicated in gene regulation. They have been recognized as drug targets for treatment of cancer and other human diseases and several inhibitors are already clinically used. Here, we report the design, synthesis, and cellular characterization of a proteolysis-targeting...
We have discovered the sirtuin rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis targeting chimera (PROTAC), enabled smal...
We have discovered the sirtuin rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD +-dependent lysine deacetylase sirtuin 2 (Sirt2). In previous studies, conjugation of a SirReal with a ligand for the E3 ubiquitin ligase cereblon to form a so-called proteolysis targeting chimera (PROTAC), enabled sma...
Because isoenzymes of the experimentally and therapeutically extremely relevant sirtuin family show high similarity, addressing the unique selectivity pocket of sirtuin 2 is a promising strategy towards selective inhibitors. An unrelated approach towards selective inhibition of isoenzymes with varied tissue distribution is targeted drug delivery or...
Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemic...
Sirtuin 1 (Sirt1) is a NAD + dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instan...
Sirtuin 1 (Sirt1) is a NAD+ dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instanc...
Lysine‐specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site‐specific LSD1 inhibition, we developed an enzyme‐prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell li...
In residence: The sirtuin rearranging ligands (SirReals) are potent and selective inhibitors of the NAD+‐dependent lysine deacetylase Sirt2 that induce target rearrangement. Our previous data with a biotinylated probe suggested a slow off‐rate as basis for potency and selectivity. The switchSENSE® technology, which is based on electrically switchab...
The Front Cover shows the X‐ray crystal structure of the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) in complex with our developed triazole‐based inhibitor. The inhibitor, whose structural formula is displayed top right, is the result of chemical modifications of the triazole‐based hit compound (top left), which w...
Objects and Summary of the Invention: "The inventors of the present invention have found compounds that inhibit KMT9, a HMT of the seven-beta-strand family. Since KMT9 inhibition is linked to a pronounced negative effect on the proliferation of specific cancer cells, the afore-mentioned compounds can be used in medicine, in particular for the treat...
Opioid receptors (ORs) have been observed as homo- and heterodimers, but it is unclear if the dimers are stable under physiological conditions. Here we use three live-cell imaging approaches to assess dimerization of ORs at different expression levels. At high membrane densities, a split GFP assay reveals that κOR dimerizes, while μOR and δOR stay...
The cell type diversity and complexity of the nervous system is generated by a network of signaling events, transcription factors, and epigenetic regulators. Signaling and transcriptional control have been easily amenable to forward genetic screens in model organisms like zebrafish. In contrast, epigenetic mechanisms have been somewhat elusive in g...
We have discovered the sirtuin‐rearranging ligands (SirReals) to be highly potent and selective inhibitors of the NAD⁺‐dependent lysine deacetylase Sirt2. Using a biotinylated SirReal in combination with biolayer interferometry, we previously observed a slow dissociation rate of the inhibitor–enzyme complex; this had been postulated to be the key t...
Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole‐based hydroxamate 2 b (N‐hydroxy‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxamide) exhibiting potent i...
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active...
Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear...
The Front Cover highlights the modus operandi of the structure‐based screening of the described tetrazole hydrazide compounds vs. human histone methyltransferase (KDM4D). The compounds were soaked one by one into the protein crystals, and the corresponding structures revealed the binding of the receptive compounds in the protein's active site. Both...
Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus Schistosoma. The disease is endemic in tropical and subtropical areas of the world where water is infested by the intermediate parasite host, the snail. More than 800 million people live in endemic areas and more than 200 million are infe...
Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell li...
Human histone demethylases are known to play an important role in the development of several tumor types. Consequently, they have emerged as important medical targets for the treatment of human cancer. Herein, structural studies on tetrazolylhydrazide inhibitors as a new scaffold for a certain class of histone demethylases, the JmjC proteins, are r...
Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginin...
The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photo...
The only drug currently available for treatment of the neglected disease Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary and urgent. To this end, the targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approa...
Recently, we have discovered the sirtuin rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase Sirt2. In previous studies, using a biotinylated SirReal analogue in combination with biolayer interferometry, we observed a slow dissociation rate of the inhibitor-enzyme comple...
The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary. Targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as promising approach. Due to the strong effects of human Sirtuin inhibitors on parasite...
Aging is characterized by the progressive loss of physiological function in all organisms. Remarkably, the aging process can be modulated by environmental modifications, including diet and small molecules. The natural compound nordihydroguaiaretic acid (NDGA) robustly increases lifespan in flies and mice, but its mechanism of action remains unclear...
Fe(II)- and 2-oxoglutarate (2OG)-dependent JumonjiC domain-containing histone demethylases (JmjC KDMs) are epigenetic eraser enzymes involved in the regulation of gene expression and are emerging drug targets in oncology. We screened a set of clinically used iron chelators and report that they potently inhibit JMJD2A (KDM4A) in vitro. Mode of actio...
The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. In this context, aromatic diazeno compounds are well suited for the design of photoswitchable ligands due to the long thermal relaxation half‐lives of the photoinduc...
By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (M...
LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study LSD1 loss of function in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features and increas...
The original version of this Article contained an error in the Acknowledgements section.
Histone lysine methylation is generally performed by SET domain methyltransferases and regulates chromatin structure and gene expression. Here, we identify human C21orf127 (HEMK2, N6AMT1, PrmC), a member of the seven-β-strand family of putative methyltransferases, as a novel histone lysine methyltransferase. C21orf127 functions as an obligate heter...
Citations
... Importantly, using a catalytically inactive mutant, we showed that prostate tumor cell proliferation depends on the enzymatic function of KMT9 [44]. Accordingly, we developed a selective small-molecule KMT9 inhibitor (KMI169) with cellular activity and provided evidence that KMT9 inhibition might be a therapeutic option for the treatment of prostate cancer [50]. ...
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... Furthermore, no significant loss of body weight was observed in mice treated with hybrid 16 (40 mg/kg; intraperitoneal injection), revealing its excellent safety profile. Further studies demonstrated that adamantane fragment was not essential for the high activity, and vorinostat-melatonin hybrid 17 (50% growth inhibition [GI 50 ]: 400 nM; Celltiter 96 R aqueous nonradioactive cell proliferation assay) also exhibited excellent activity against MCF-7 breast cancer cells [46]; movement of the hydroxamic acid motif from the N-1 position of the indole moiety to the C-5 position was also tolerated, as evidenced by the fact that hybrid 18 (GI 50 : 300 nM; Celltiter 96 aqueous nonradioactive cell proliferation assay) showed remarkable activity against MCF-7 breast cancer cells, and the activity was superior to that of vorinostat (GI 50 : >1.0 μM) and melatonin (GI 50 : >1.0 μM) [46]. In addition, hybrids 17 (IC 50 : 55 and 30 nM) and 18 (IC 50 : 21 and 5.0 nM) also possessed higher inhibitory activity than vorinostat (IC 50 : 126 and 58 nM) against HDAC1 and HDAC6. ...
... A challenging issue related to sirtuin isoform 2 (SIRT2) specifically is that small molecules with good isoform selectivity and nM potency often inhibit its deacetylase activity without affecting its defatty-acylase/demyristoylase activity [16,17]. Some exceptions to this include a peptide macrocycle inhibitor of SIRT2 and peptide-like, mechanism-based SIRT2 inhibitors that affect its demyristoylase activity; however, these peptide-like compounds generally lack drug-like qualities [18][19][20][21][22]. Newly identified molecules of the "SirReal" class have shown the most promise as SIRT2 demyristoylase inhibitors with potencies in the mid nM to low μM range [23,24]. However, other small molecules that inhibit SIRT2's demyristoylase activity have lower selectivity or potency and include ascorbyl palmitate (IC 50 =~8 to 23 μM) [25], 1-aminoanthracene (IC 50 = 21 μM) [12], "compound C" (IC 50 = 44 μM) [26], and suramin (IC 50 = 95 μM) [27]. ...
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... We evaluate our method on the bromodomain-containing protein 4 (BRD4, PDB:7r5b [69]), a protein involved in the development of a specific type of cancer (NUT midline carinoma) [22] and targeted by pharmaceutical drugs [14]. For a given number m, we randomly sample m pairs of alpha carbons (without redundancy) between which we assume the distances to be known. ...
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... Also in 2015, a phase I study was initiated to investigate the sensitization of non-M3 AML blasts to ATRA using TCP (NCT02717884). In this trial, the administration of TCP in combination with ATRA and low-dose cytarabine (LDAC) was well feasible in elderly, medically nonfit AML/MDS patients resistant to prior hypomethylating agents (HMA) treatment even at the highest TCP dosage.141 ...
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... The latest study describing the synthesis of HDAC6 targeting PROTACs comes from the Sippl group 52 . They designed PROTACs based on the previously synthesized HDAC6 selective inhibitors, benzohydroxamates TH74 and SD100NC. ...
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... Therefore, SmHDAC8 has been proposed as a promising target for drug discovery [10]. In recent years, both our group and other research teams have identified HDAC inhibitors that demonstrated effectiveness against S. mansoni and/or impacted the enzymatic activity of S. mansoni HDAC8 (SmHDAC8) [13][14][15][16][17][18][19][20][21][22]. Most discovered inhibitors active on SmHDAC8 present a zinc-binding group, such as a hydroxamate or a sulfur moiety [17]. ...
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... Darwish et al. designed PROTACs based on benzhydroxamates, with low nanomolar range inhibitory activity against HDAC8, combined with either CRBN or VHL ligands 55 . The selectivity of benzhydroxamates can be related to the fact that the aromatic capping group occupies an HDAC8-specific pocket, which is lacking in the other HDAC isoforms. ...
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... 4,5 In contrast to other neglected tropical diseases such as malaria and tuberculosis, support for the discovery of new oral antischistosomal therapeutics has, until now, been limited and during the past four decades, no new chemical entity has progressed into clinical development. 6 Testing compounds against molecular targets such as histone deacetylases (HDACs) 7,8 and histone acetyltransferases (HATs), 9 venus kinase receptors (VKRs), 10 lysine-specific demethylases (LSDs) 11 and transient receptor potential (TRP) channels 12 among others has shown some success in identifying potential leads with ex vivo and/or in vivo activity. In light of limited validated drug anti-schistosomal targets, phenotypic screening of FDA-approved drugs, natural products and structurally diverse chemical libraries from pharmaceutical companies, charitable organizations and commercial sources has been the preferred approach to generate new chemical starting points for developing alternative therapies. ...
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... However, due to its poor solubility, low oral bioavailability, and susceptibility to degradation, balsalazide is not considered a viable candidate for a targeted SIRT5 small molecule drug. Consequently, Glas et al. have performed structural modifications on the core azo moiety of balsalazide based on structure-activity relationship analysis, aiming to enhance the inhibitory activity against SIRT5 while retaining selectivity, resulting in two potential SIRT5 inhibitors, CG-220 and CG-232 [121]. Among the SIRT5 modulators for tumor therapy mentioned above, MC3183 is the only small-molecule activator specifically targeting SIRT5 (Fig.3). ...
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